title: Targeting SRC and tubulin in mucinous ovarian carcinoma.
abstract: OBJECTIVE
  To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma.
  
  
  METHODS
  The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models.
  
  
  RESULTS
  In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2-M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules.
  
  
  CONCLUSIONS
  Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma.
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Genitourinary Medical Oncology, Bioinformatics and Computational Biology, and Cancer Biology; Division of Cancer Medicine; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas; Kinex Pharmaceuticals LLC, New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York; Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei; Department of Gynecology, Obstetrics and Gynecology, Hospital of Fudan University, Shanghai, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dalton
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Yu
authors.initials: Y
authors.lastname: Kang
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.forename: Takahito
authors.initials: T
authors.lastname: Miyake
authors.forename: Jian H
authors.initials: JH
authors.lastname: Song
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wen
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zand
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.forename: David G
authors.initials: DG
authors.lastname: Hangauer
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Michael
authors.initials: M
authors.lastname: Frumovitz
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000378:metabolism; D009025:Morpholines; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077150:Oxaliplatin; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D055503:Protein Multimerization; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D009025:Morpholines; D009944:Organoplatinum Compounds; D011725:Pyridines; D050257:Tubulin Modulators; C000713668:tirbanibulin; D000077150:Oxaliplatin; D019061:src-Family Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human